The proportion of persons living with HIV/AIDS who are over 50 rose to 22.5% of all cases in 2004. Our lack of understanding about how age and HIV/AIDS interact is becoming increasingly problematic, no more so than in the area of the neurocognitive manifestations of AIDS, since age is itself an important predictor of neurocognitive syndromes. In spite of the known links between age and various neuropsychiatric disorders including dementia, only recently has much attention has been paid to the possible interactions between HIV disease, aging and neuropsychiatric presentation. The purpose of this application is to obtain funding to compare and contrast brain structural and functional abnormalities associated with HIV/AIDS as a function of cardiovascular abnormalities. As the rate of cardiovascular disease increases with age, so too do the consequences of those disorders including abnormalities in the small vessel in the brain, decreased grey matter volume, altered white matter integrity, and changes in regional cerebral blood flow. Understanding how these normal consequences of aging are affected by HIV is important for clinical care, the development of new treatment strategies, and understanding the pathophysiology of HIV-Associated Neurocognitive Disorder. We will evaluate the cardiovascular, cognitive, and brain structure/function status of 340 men participating in the cardiovascular substudy of the Multicenter AIDS Cohort Study (MACS). We will take advantage of the nearly 25 years of prior clinical and neuropsychological data, combined with the new CVD variables (e.g., coronary calcium, carotid intima-media thickness) and MRI findings (anatomic, diffusion imaging, blood flow, and spectroscopy) to address a series of linked hypotheses concerning brain structural and functional abnormalities, and their relationship to CVD variables, HIV serostatus, and markers of the severity of the HIV infection. The MACS is accumulating evidence of the importance of medical comorbidities as risk modifiers for the clinical expression of a neuropathological process, likely due to a decrease in cognitive reserve. We will evaluate this model by using both cross-sectional and longitudinal data from the study participants who range in age from 50 to 75 years old. We will test the hypothesis that small vessel disease and its consequences not only alter brain structure and function, but by doing so, decrease brain/cognitive reserve, allowing the effects of HIV disease to be expressed earlier, and at a less severe clinical stage. If this hypothesis is supported it could potentially alter the way in which we approach the treatment of HIV disease among patients with access to appropriate medical management. We propose that HIV and CVD have direct effects on brain structure/function, and that CNS integrity is the direct link to cognitive functions; CVD is itself predicted by advancing age. We predict that HIV infection moderates the strength of the pathway between CVD and brain structure. That is, the effects of CVD on brain structure/function will be augmented in the HIV-infected men relative to the uninfected men.